tbuckley/cabot-search huggingface dataset:
Systematic literature review and meta-analysis of clinical outcomes for previously treated patients with advanced gastric or gastroesophageal junction cancer.
Authors: Lauren Abderhalden, Andrew Frederickson, Brain M Lang, Ali Mojebi, Ping Wu, Alexander Gozman, William Malbecq, Fan Jin, Mayur Amonkar
Journal: Journal of Clinical Oncology (2022)

e16054 Background: Standard of care treatment in advanced (unresectable and/or metastatic) gastric or gastroesophageal junction (GEJ) cancer includes chemotherapies with or without targeted therapies. While there have been many studies undertaken in this patient population, there exists uncertainty around the efficacy of these treatments. A systematic literature review and meta-analysis were conducted to assess clinical outcomes of chemotherapies with or without targeted therapies. Methods: A systematic literature review was conducted through mid-2021 to identify relevant studies using Embase, MEDLINE, and Cochrane Central Register of Controlled trials (January 1, 2000–July 6, 2021) with additional searches of recent annual ASCO and ESMO conferences. Eligible studies included randomized controlled trials (RCTs), controlled clinical trials, and non-randomized clinical trials of any pharmacologic treatments licensed by the FDA or EMA among patients (≥18 years age, Eastern Cooperative Oncology Group performance score 0 or 1) previously treated for advanced gastric or GEJ cancer and who had progressed on prior treatment (i.e., ≥2L). A meta-analysis of objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were conducted among RCTs of relevant therapies for ≥2L gastric cancers. The ORR meta-analysis was performed using the Freeman-Tukey double arcsine transformation. For time-to-event outcomes, published Kaplan-Meier curves for OS and PFS were digitized to create pseudo- individual patient data. A meta-analysis of the resulting pooled survival curves for OS and PFS were conducted following the methodology of Combescure et al. (2014). Results: Of the 214 studies identified, 42 RCTs (77 trial arms) evaluating relevant therapies including 7,256 participants were included in the meta-analysis of ORR. The random effects pooled estimate of ORR was 15.0% (95% confidence interval [CI]: 12.7-17.5%). Median PFS (32 studies; 61 survival curves) was 3.5 months (95% CI: 3.2-3.7) with PFS rates at 6, 12, and 24 months of 25.8% (95% CI: 23.1-28.8%), 7.3% (95% CI: 6.0-8.9%), and 0.7% (95% CI: 0.4-1.0%), respectively. Median OS (34 studies; 64 survival curves) was 7.9 months (95% CI: 7.4-8.5) with OS rates at 6, 12, and 24 months of 62.5% (95% CI: 59.0-66.2%), 30.4% (95% CI: 27.7-33.3%), and 6.7% (95% CI: 5.4-8.4%), respectively. Conclusions: The standard treatments have demonstrated limited efficacy in previously treated patients with advanced gastric or GEJ cancers. Newer treatments (e.g., immunotherapies) to address this unmet medical need should be thoroughly investigated and evaluated.
A lean-sprint approach to protocol development.
Authors: Varun Paul, Lori Ferranti, David M. Dilts
Journal: Journal of Clinical Oncology (2022)

e18639 Background: With the ever-increasing complexity of protocols and their required approvals, there is a need to improve the time and reduce the effort required to create a Phase III protocol. The objective of this research was to reduce from months to weeks the time to create a Phase III protocol at a large global pharmaceutical organization, while maintaining or improving the quality and scientific merit of the protocol. Methods: The method required two phases: process redesign and process execution/performance. For the first phase, a continuous improvement methodology (Lean), was utilized. In a multi-team-based approach, the first stage (process-prep) focused on the development of the initial draft protocol. The second stage used the concept of a Sprint, a process to complete all protocol changes and approvals within a rapid time span, while simultaneously guaranteeing protocol quality. A set of policies, procedures, and information technology tools were developed to facilitate both efforts. The Process-prep stage was team-based, where a streamlined Clinical Study Team and a sub-group, the Protocol Working Group, identified all the key tasks, activities and their associated completion dates, and created an 80% complete draft protocol. The Sprint was a one-week, intensive effort by all those responsible for creation of the protocol, and for its final approval. Working virtually and internationally allowed for a continuous 24-hour effort during the Sprint. One key element of success was the use of a visualization tool for the creation, adaptation, and finalization of the protocol’s schedule of assessments (SOA) which both assured that all assessments were required by the protocol and that there was concordance between the protocol and the SOA. Results: Quantitative results were significant: a completed protocol was created with a 50% reduction of time compared to the last protocol written by the molecule group, reduction of avoidable amendments, reducing missed errors and potentially decreasing the number of protocol amendments and the near elimination of process loops and email-chains. Qualitatively, team members were trained on useful process tools and methods, while also increasing their comfort level in active participation in remote meetings. This resulted in faster time to create any amendments that may be required in the future for the protocol. Conclusions: It is possible to employ efficiency and effectiveness methods, such as Lean and Sprint, that have been used successfully in other industries in the pharmaceutical research &amp; development process. While using such concepts requires a great deal of initial planning, the rewards of using them are significant. Likewise, the extensive use of interdisciplinary remote teams will be of increasing importance in a post-COVID environment of clinical research.
Spine high-grade osteosarcoma in the era of radiotherapy with high-energy charged particles: A single institution retrospective analysis.
Authors: Gisberto Evangelisti, Luigi Falzetti, Emanuela Palmerini, Marco Cianchetti, Joseph H. Schwab, Stefano Boriani, Toni Ibrahim, Alessandro Gasbarrini
Journal: Journal of Clinical Oncology (2022)

11532 Background: Limited are data on high-grade osteosarcoma occurring in the spine. Wide resection is recommended, but it is a difficult and high morbidity procedure in the spine. High-energy particle therapy has been recently used. The goal of this study was to examine treatment and outcome of patients with osteosarcoma in the mobile spine. Methods: Spine high grade osteosarcoma patients who underwent surgery at the Rizzoli Institute between 2009 and 2020 were identified. Treatment, outcome, and prognostic factors in patients treated in a single institution were examined. Results: Characteristics of the 20 patients (8 female; 12 male) included: median age, 39.7 years (range, 14-71 years), 5 (25%) with tumors in the cervical spine, 6 (30%) with tumors in the thoracic spine, and 9 with tumors in the lumbar spine (45%); 14 (70%) patients with localized disease and 6 (30%) with metastatic disease at the time of presentation. Nineteen patients (95%) underwent chemotherapy, the majority were treated with MAP (methotrexate, doxorubicin, cisplatin) regimen. In 12 patients undergoing preoperative chemotherapy (n = 11) or chemotherapy and radiotherapy (n = 1), the median tumor % necrosis was 20 (IQR 20 - 40), with none achieving a good histologic response (&gt; 90%). All patients underwent surgery. Adequate surgical margins were achieved in 5 patients (25%). In patients with positive margins, radiotherapy was administered to 8 (40%) patients. Four patients with positive margins after resection received photon neoadjuvant or adjuvant therapy. Four patients received high-energy particles as adjuvant therapy after planned gross total excision. The median overall survival rate was 10.5 months (IQR 5.8 - 15.0) for patients with metastatic disease and 25.5 months (IQR 8.3 - 46.0) for patients with localized disease (P =.0501). Patients treated with planned intralesional gross total resection followed by adjuvant high-energy particle therapy had a significant higher disease-specific survival than patients with positive margins after resection with or without additional conventional radiotherapy (P =.023). Conclusions: Metastatic disease, is a poor prognostic factor for high grade osteosarcoma of the spine. Post-operative high-energy particle therapy improved overall survival in patients undergoing a planned gross total resection compared to intralesional resection in this series. Chemotherapy induced necrosis was low underscoring the need of more aggressive multidisciplinary approaches for these patients.
Prognostic values of immune landscape in Ras-mutant colorectal cancer peritoneal metastases.
Authors: Dong Yan, Lixin Sun, Jiandong Yang, Xuyang Zhang, Xia You, Tingting Sun, Chuang Qi
Journal: Journal of Clinical Oncology (2022)

e15583 Background: The peritoneal metastasis (PM) in patients with colorectal cancer (CRC) is associated with poor survival, especially in those with Ras mutations. However, knowledge on the mechanism of molecular biology in CRC peritoneal metastasis (CRCPM) is limited, and the impact of tumor immune microenvironment (TME) on PM pathogenesis and the prognosis of CRCPM remain unclear. Therefore, we characterized the TME of CRCPM and evaluated its potential diagnostic and prognostic values. Methods: This study involved 21 patients with metastatic CRC (mCRC), of whom 11 with CRCPM were classified into the experimental group and 10 with mCRC without PM (noCRCPM) were classified into the control group. Formalin-fixed and paraffin-embedded tissue of primary tumors from all patients was examined using the NanoString RNA sequencing system. The clinicopathological variables and TME biomarkers were compared using the chi-square test and Cox regression analysis. According to the results of multivariate analysis, a prognostic nomogram was generated, and its prediction ability was measured using the concordance index (C-index). Survival curves were generated using the Kaplan–Meier method, and survival comparison between groups was conducted using the log-rank test. Results: The TME in the CRCPM and noCRCPM groups was different, especially the expression of NOS2, TNSF9, KIR3DL2, MAGEA12, MRC1, KIR3DL1, and CD244 and the content of DC cells, macrophages, exhausted CD8+T cells, NK CD56dim cells, and M2 macrophages. Univariate analysis revealed that the expression of PTPN11, TIE1, MAGEA4, PDGFB, and PMS2 was significantly correlated with progression-free survival (PFS) time. These genes were subjected to the least absolute shrinkage and selection operator regression analysis and established a risk score model. Multiple Cox regression analysis showed that the risk score was a significant independent prognostic factor. However, considering the particularity of serum carcinoembryonic antigen (CEA), we built a combined model that included the CEA level and risk score. It could perform well in predicting the PFS time in patients with CRCPM (C-index 0.77). Conclusions: The TME of the primary lesion was significantly different between the CRCPM and noCRCPM groups. The model that combined the risk score and CEA level was a better outcome predictor among patients with CRCPM.
Is It Exposure to the Pandemic or to Maternal SARS-CoV-2 Infection That Is Adversely Affecting Early Childhood Neurodevelopment?
Authors: Torri D. Metz
Journal: JAMA Network Open (2022)

Andrea G. Edlow, MD, MSc; Victor M. Castro, MS; Lydia L. Shook, MD; Anjali J. Kaimal, MD, MAS; Roy H. Perlis, MD, MSc
Providing care for those fleeing war: challenges and solutions for Polish doctors looking after refugees from Ukraine
Authors: Mateusz Babicki, Agnieszka Mastalerz-Migas
Journal: BMJ (2022)

The ongoing armed conflict in Ukraine has caused the biggest migration crisis Europe has faced in the 21st century.Over this period, more than seven million people have fled the country, the largest number of which have come to Poland-almost four million according to the United Nations High Commissioner for Refugees. 1 The Polish Parliament passed a special law in March that allows war refugees from Ukraine to access many public benefits, including free healthcare, as well as the reimbursement of medicines and medical products on the same terms as people insured in Poland.
Do SPECT CT and sentinel node tecnhique increase the diagnosis of metastasic disease in prostate cancer?
Authors: J. Perez Ardavin, M. Martínez-Sarmiento, J.J. Monserrat-Monfort, J.V. Sánchez-González, V. Vera-Pinto, P. Sopena-Novales, P. Bello-Arqués, F. Boronat-Tormo, C.D. Vera-Donoso
Journal: European Urology (2022)
TRUCE-02: An open label, single-arm, phase II study of tislelizumab combined with nab-paclitaxel for high-risk non-muscle-invasive urothelial bladder carcinoma.
Authors: HaiTao Wang, Hailong Hu, Yuanjie Niu, Dawei Tian, Chong Shen, La Da, Zhouliang Wu, Gangjian Zhao, Diansheng Zhou, Yiduo Bai, Houyuan Chen
Journal: Journal of Clinical Oncology (2022)

4507 Background: Pts with multiple or tumors with large invasion areas which are un-completely-resectable through TURBT would be recommended radical cystectomy in the clinical treatment. The KEYNOTE-057 study has illuminated the efficiency of immune checkpoint inhibitors monotherapy in HR-NMIBC pts, with acceptable adverse events (AEs). However, the role of PD-1/PD-L1 inhibitor in combination with chemotherapy in NMIBC pts remains unclear. We report preliminary treatment efficiency, safety data, and exploratory work of TRUCE-02 trial. Methods: TRUCE-02 is a phase II study for NMIBC pts with uncompletely resectable tumour by TURBT. The primary endpoint was complete response(absence of non-muscle-invasive bladder cancer or progressive disease). Pts that meet the criteria would receive tislelizumab 200mg on days 1 plus paclitaxel 200mg on days 2 every 3 weeks (Q3W) x 3 or 4 cycles followed by a comprehensive assessment including pathology, urine cytology, and imageology. Meanwhile, biomarker analyses included programmed death-ligand 1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 pharmDx assay) and whole transcriptome RNA sequencing of the tumor. Results: Between July 2020 and January 2022, 54 pts were enrolled. 42 pts have completed whole 3 or 4 treatment cycles and reached the primary endpoint. 23 pts achieved CR condition (56%, 95%CI, 43.6% and 74.4%). ORR of 60% (N=25/42, 95%CI, 45.2% and 74.8%). As a secondary endpoint, 33 pts remain cystectomy-free condition (78.6%, 95%CI, 66.2% and 91%). Grade 3-4 AEs were lower than 2%. Urine cytology showed its diagnostic efficiency of 68.42% (95%CI, 61.3% and 75.6%), urine FISH showed a diagnostic efficiency of 45.71% (95%CI, 37.7% and 53.4%) before pathological assessment. As for PD-L1 expression, 47.3% (N = 9/19) of response pts (CR+PR) showed positive, 50% (N = 5/10) of un-response pts (PD+SD) showed positive. We also found out through sequencing results that AR, TCF7L2 might be underlying markers that predict adverse outcomes for pts in this crew. HRR mutation may predict a positive prognosis and mutations in NMIBC which might predict the prognosis of this treatment plan. Conclusions: Tislelizumab with nab-paclitaxel represents a novel treatment option with a satisfactory benefit in treating NMIBC. PD-L1 expression has no obvious correlation with the efficiency of this treatment plan. WGS result also showed that there are mutation markers that may predict whether pts would benefit from this treatment plan. Clinical trial information: NCT04730232. [Table: see text]
RARE-08. Profiling of recurrent adamantinomatous cranionpharyngioma confirms the activation of the MAPK pathway and identifies copy number aberrations in relapsed tumours
Authors: John Apps, Jessica Pickles, Thomas Stone, Jane Chalker, Olumide Ogunbiyi, Edward Schwalbe, Sebastian Brandner, Georg Otto, Sergi Castellano, Thomas Jacques, Timo Deutschbein, Juan Pedro Martinez-Barbera
Journal: Neuro-Oncology (2022)

Abstract Craniopharyngiomas are rare challenging tumours, with around 25% of cases recurring despite surgery and/or radiotherapy. Whilst transcriptomic and proteomic profiling of adamantinomatous craniopharyngioma (ACP) have revealed activation of the MAPK pathway and IL-6 mediated inflammation, relatively little is known about the biological processes involved in tumour recurrence. To address this, we have analysed a cohort of primary and relapsed ACP tumour accessed from tissue banks, local pathology departments and international collaborators. Serial samples of recurrent ACP (n=11), recurrent papillary craniopharyngioma (PCP) (n=4) and 3 non-recurrent ACP were analysed using β-catenin, pERK1/2 immunostaining, DNA methylation array and RNA sequencing. Differential expression and methylation analyses confirmed differences between ACP and PCP, with over representation of WNT pathway genes in ACP and the MAPK pathway genes in PCP. All of the primary and all except for one of the relapsed ACP tumours showed a pERK1/2 expression. Differences in the immune environment were also identified between ACP and PCP, with higher levels of some inflammatory mediators and CD14+ cell signatures in PCP compared with ACP. Whilst differential methylation and expression analysis revealed relatively stable methylomes and transcriptomes between serial samples of cases, segmental chromosomal alterations were identified in recurrence samples from five ACP cases (5/11,45%). One relapsed case showed histological and molecular signs of malignant transformation, including high ki67 and deletion of TP53. Surprisingly, this malignant tumour showed nuclear beta-catenin in all neoplastic epithelial cells and absence of pERK1/2 staining, despite the primary tumour showing the typical beta-catenin and pERK1/2 expression patterns. These results suggest that the molecular landscape of craniopharyngioma remains stable between recurrences in most cases, but, there is evidence of molecular evolution in a subset of cases. Activation of the MAPK pathway in the vast majority of ACP tumours supports the clinical evaluation of MAPK pathway inhibitors in ACP patients.
Gut bacterial isoamylamine promotes age-related cognitive dysfunction by promoting microglial cell death
Authors: Yun Teng, Jingyao Mu, Fangyi Xu, Xiangcheng Zhang, Mukesh K. Sriwastva, Qiaohong M. Liu, Xiaohong Li, Chao Lei, Kumaran Sundaram, Xin Hu, Lifeng Zhang, Juw Won Park, Jae Yeon Hwang, Eric C. Rouchka, Xiang Zhang, Jun Yan, Michael L. Merchant, Huang-Ge Zhang
Journal: Cell Host & Microbe (2022)
MEDB-72. MOLECULAR CHARACTERIZATION OF MEDULLOBLASTOMAS IN A SINGLE INSTITUTION
Authors: Enrica E K Tan, Mui Li Tan, Chik Hong Kuick, Min Hwee Yong, Sharon Y Y Low, Kenneth T E Chang, Char Loo Tan
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: The four molecular groups (WNT, SHH, Group 3 and Group 4) in medulloblastoma have been well established for the past decade. New subgroups within the four principal molecular groups have recently been discovered and recognized by WHO classification of Central Nervous System Tumours (5th edition). Subgroups were reported to have distinct somatic copy-number aberrations and clinical outcomes. This further classification could be helpful to refine prognostication and potentially provide risk stratification for treatment planning. AIM: To interrogate archival medulloblastoma samples using Oncoscan Microarray Assay, correlate with clinical features and consider the assay for clinical use. METHODS: Thirty-one archival samples with histological diagnosis of medulloblastoma and molecular grouping results from NanoString were retrieved and evaluated with Oncoscan Microarray Assay. Twenty-six were subjected to DNA methylation profiling to compare the results. Eight cases also had molecular data from next-generation sequencing (NGS) done with the in-house Ampliseq Childhood Cancer Panel. Correlation was made with clinical characteristics and outcomes of these 31 patients. RESULTS: OncoScan microarray showed distinct differences in the copy number profiles of the 31 medulloblastoma samples. Seventeen samples could be further classified into one of 12 subgroups. However, further subgrouping was challenging without first determining the main molecular group especially amongst non-WNT/SHH tumours. DNA methylation results provided corroboration with the Oncoscan subgrouping results in 25 of 26 samples. NGS panel detected additional genetic alterations in 5 of 8 samples. CONCLUSIONS: Oncoscan Microarray Assay showed potential in providing additional molecular information for further subgrouping of medulloblastoma, but was insufficient for determining the main molecular groups. Moving forward, molecular characterization could instead be done through use of NGS panel and DNA methylation, which provides tumour epigenetic profiling on top of copy number variants. These could be used alongside the NanoString platform, which is performed routinely for all medulloblastomas at our centre.
Implementing proven methods in a community-based health system to improve breast cancer screening rates during the COVID-19 pandemic.
Authors: Celine Fadel, Shivang Danak, Andria P Caton
Journal: Journal of Clinical Oncology (2022)

6565 Background: There are reduced screening rates across the United States secondary to the COVID-19 pandemic; the additional anticipated deaths from breast and colorectal cancer, secondary to reduced screening, is approximated at 10,000 people. A study of thirty-two health systems in Georgia noted an 8% decrease in screening mammography compared to pre-pandemic rates. To help reverse the decline, Northeast Georgia Medical Center (NGMC) participated in the "Return to Screening" initiative, in conjunction with the American Cancer Society (ACS). A quality improvement project was performed at the community-based hospital system to increase breast cancer screening rates, using a multidisciplinary approach with a focus on health care disparities. Methods: The initial goal was to increase screening mammograms by 10% (n = 14,364) from June 1 st to December 1 st 2021. Interventions were selected by a multidisciplinary team of NGMC researchers, clinical providers, and oncology administrators. Interventions varied in category, encompassing unique patient and provider-specific approaches. The evidence-based interventions were tailored to address health care disparities in the local population. This included identification and quantification of cultural groups in the community to ensure quality patient access. Integrative collaboration consisted of intermittent meetings to certify consistent communication, project reflection and identification of barriers. The selected interventions were executed monthly, with simultaneous data tracking of mammography rates. Results: From June 1 st to December 1 st 2021, a total of forty evidence-based interventions were successfully implemented. Analysis of screening rates demonstrated a 15% increase across the allotted time period, corresponding to an average of 1,302 mammograms monthly (n = 15,284). This exceeded the initial anticipated goal of increasing screening by 10% (n = 14,364). Analysis of mammography results identified 331 new cases of breast cancer diagnosed within the allotted period, a 7% mean diagnosis rate increase. Certain planned interventions were unable to be conducted and required modification due to limitation of the ongoing pandemic; however, this solidified the use of social media and virtual participation as effective methods of community outreach. Conclusions: We identified key methods to engage the local community and successfully increased rates of screening mammography. Interventions were tailored to the local population, ensuring patient-centered tools and a personalized approach to medicine. The multidisciplinary, consistent collaboration with stakeholders ensured quality of care for the local patient population. This project demonstrates the importance of local community engagement to impact national cancer screening rates, and thus, ensure earlier detection of breast cancer.